Hyperthyroid Graves' disease (GD) and Graves' Orbitopathy are associated with the development of autoantibodies to the TSH receptor (TSHR-Ab) which act as TSH agonists and activate TSHR signal transduction. The purpose of this application is: 1: To develop our lead small molecule agonists to the TSHR. To do this we will use a chemical modification strategy and examine the signaling pathways of the higher affinity analogs both in vitro (thyroid cells) and in vivo (mice). 2. We will use both a virtual and computational screening strategy and a high throughput assay to identify and characterize additional small molecules stimulating or blocking the TSHR 3. We will continue our studies of neutral TSHR monoclonal antibodies as TSHR modulators by using them in vivo in mice to characterize their influence on thyroid function and thyroid cell apoptosis.. 4. We will characterize human neutral antibodies to the TSHR in patients with Graves' disease and their role in the induction of thyroid cell apoptosis in vitro with a view to their potential as regulators of thyroid function in this disorder. The insight gained from these studies will have tremendous potential in furthering our understanding of the role of the TSHR in Graves' disease and of developing useful receptor regulators with therapeutic potential.